Variations in 5-fluorouracil concentrations of colorectal tissues as compared with dihydropyrimidine dehydrogenase (DPD) enzyme activities and DPD messenger RNA levels.

Abstract

Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in 5-fluorouracil (5-FU) catabolism. We measured DPD activities represented as DPD protein levels (units/mg protein) and the associated mRNA levels in tumorous and normal tissues from 40 colorectal cancer patients, and we studied the relation to 5-FU concentrations in the same samples after treatment with doxifluridine, a prodrug of 5-FU. DPD mRNA levels were also measured in biopsy samples before treatment for comparison with those in surgical samples. 5-FU concentrations in tumors were higher than those in normal tissues (P < 0.05) and were inversely associated with DPD protein levels (r = -0.463; P < 0.05). DPD activities in tumorous and normal tissues showed a significant correlation (r = 0.527; P < 0.01). DPD protein levels correlated with their mRNA levels detected by semiquantitative reverse transcription-PCR in tumor tissues (r = 0.740; P < 0.01). DPD mRNA levels in tumor biopsy specimens correlated with those in surgical specimens (r = 0.366; P < 0.05). These results suggest DPD activities in tumors to be predictive of 5-FU levels in colorectal cancer tissues and are reflected by DPD mRNA levels as measured by reverse transcription-PCR.